CASE REPORTS Rhabdomyolysis Following Cardiopulmonary Bypass and Treatment with Enoximone in a Patient Susceptible to Malignant

Ⅵ CASE REPORTS

Anesthesiology 2001; 94:355–7 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Rhabdomyolysis following Cardiopulmonary Bypass and Treatment with Enoximone in a Patient Susceptible to Malignant Hyperthermia Friedrich-Christian Riess, M.D.,* Marko Fiege, M.D.,† Sina Moshar, M.D.,‡ Heinz Bergmann, M.D.,§ Niels Bleese, M.D.,ʈ Joachim Kormann, M.D.,# Ralf Weißhorn, M.D.,† Frank Wappler, M.D.††

SEVERE hypercapnia, muscle rigidity, hyperthermia, and After implantation of a mechanical valve (Medtronic Hall; Medtronic, rhabdomyolysis characterize malignant hyperthermia Minneapolis, MN), the ascending aorta was closed and the aortic 1 cross-clamp removed. During reperfusion, the patient exhibited ST (MH) in fulminant form. However, during cardiac opera- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 elevations, with maximal values of 12 mV in all leads. The left ventricle tions using cardiopulmonary bypass (CPB), typical symp- appeared to be ischemic and hypokinetic. A triple bypass was per- toms of MH may not be present. We observed a patient formed using saphenous grafts to the left anterior descending, first undergoing aortic valve replacement, in whom severe post- diagonal branch and the circumflex artery. The patient was then operative rhabdomyolysis and arrhythmias developed after successfully weaned from CPB using a moderate dose of adrenalin (4 ␮ treatment with enoximone during CPB and cardioplegic g/min) and 50 mg enoximone (Perfan; Hoechst, Bad Soden am Ts., Germany). However, toward the completion of the operation, the arrest. Subsequently, in vitro contracture testing showed urine became dark and the minute ventilation necessary to maintain that the patient was susceptible to MH. normocapnia were increased from 8 to 14.2 l/min, whereas pH decreased to 7.19. On the first postoperative day, a potassium concentration of 6 mM, Case Report a CK concentration of 9,348 U/l, and an increase of creatinine concentration to 2.5 mg/dl were noted. Rectal temperatures remained normal. A 48-yr-old man (weight, 92 kg; height, 169 cm) was scheduled to Ventricular arrhythmias and atrial fibrillation occurred on the second undergo aortic valve replacement. Family history was unremarkable. postoperative day, and administration of increasing amounts of intra- No allergies to medications were known. There was no history of venous adrenalin was necessary to achieve hemodynamic stability. A surgery or anesthesia. Enalapril (Pres; Boehringer, Ingelheim, Ger- serum myoglobin concentration of 8,887 ␮g/l was noted. There were many) 10 mg/day was the only preoperative medication. Laboratory no signs of compartment syndrome in any extremity. Because malig- data were normal except for a ␥ glutamate transferase of 41 U/l nant hyperthermia was suspected, the patient was treated with 220 mg (normal, Ͻ 28). Creatine kinase (CK) concentration was 53 U/l. dantrolene (Dantrolen; Procter & Gamble Pharmaceuticals, Weiters- The patient received 2 mg flunitrazepam (Rohypnol; Hoffmann La- tadt, Germany) intravenously. The hemodynamic profile of the patient Roche, Basel, Switzerland) orally the evening before surgery and an- improved, and catecholamine therapy could be discontinued. Because other 2 mg flunitrazepam and 0.3 mg clonidine (Catapresan; Boehr- of renal impairment, hemofiltration was started and was continued for inger) orally on the morning of surgery. Anesthesia was induced using 19 days. On the third postoperative day, a second dose of 25 mg 1 mg/kg intravenous propofol (Disoprivan; Zeneca, Plankstadt, Ger- enoximone was administered. Shortly thereafter, partial pressure of many) and 25 ␮g intravenous sufentanil (Sufenta; Janssen, Neuss, Germa- carbon dioxide (PCO2) increased to 48.3 mmHg during mechanical ny), muscle relaxation was achieved using 0.2 mg/kg intravenous pancu- ventilation, and CK concentration increased to 9,348 U/l. This re- ronium bromide (Pancuronium; Curamed Schwabe, Karlsruhe, Germany). sponse was treated again with 220 mg dantrolene intravenously. Pa- Ϫ1 Ϫ1 Anesthesia was maintained using propofol (4 mg ⅐ kg ⅐ h ) and tient serum muscle enzyme concentrations gradually returned to nor- Ϫ1 Ϫ1 sufentanil (0.5 ␮g ⅐ kg ⅐ h ). The patient received 2 g cephazolin mal, and he was discharged in good condition on the thirty-third sodium (Gramaxin; Boehringer, Mannheim, Germany) intravenously. A postoperative day. membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany) was Five months postoperatively, the patient was examined for malig- used together with a roller pump. The priming solution of CPB (1,600 nant hyperthermia susceptibility and other muscular diseases. After the ml) contained lactated Ringer’s solution, mannitol (15%), and sodium patient had given informed consent, muscle biopsy was performed bicarbonate, and 5,000 IU unfractionated heparin (Heparin Braun; using regional anesthesia. The muscle bundle was excised carefully Braun Melsungen, Melsungen, Germany) and aprotinin (Antagosan; from the vastus lateralis muscle, and an additional small muscle sample Behringwerke AG, Marburg, Germany). Standard CPB was established was obtained for evaluation of histomorphologic changes. ⅐ Ϫ1 ⅐ Ϫ2 with a flow rate of 2.5 l min m , which was reduced during The in vitro contracture tests (IVCTs) with halothane and caffeine ⅐ Ϫ1 ⅐ Ϫ2 hypothermia to 2.0 1 min m at 34.2°C (rectal temperature). were performed according to the protocol of the European Malignant Hyperthermia Group (EMHG).2 The muscle bundle was dissected into eight strips. Only viable muscle samples (twitch response to supra- * Associate Professor of Cardiac Surgery, ‡ Resident, ʈ Professor and Head, maximal electrical stimulation Ͼ 10 mN) were used. Two samples Department of Cardiac Surgery, § Staff Anesthesiologist, Department of Anesthe- were tested with each drug. The muscle specimens of this patient siology, # Anesthesiologist and Head, Department of Cardiac Anesthesiology, Albertinen-Hospital. † Staff Anesthesiologist, †† Associate Professor of Anesthe- developed abnormal contracture responses to 0.44 mM halothane and siology, Department of Anesthesiology, University-Hospital Eppendorf. 2.0 mM caffeine, indicating susceptibility to MH. After administration of ␮ Received from the Departments of Cardiac Surgery, Anesthesiology, and Cardiac 1 M ryanodine, an accelerated and increased contracture develop- Anesthesiology, Albertinen-Hospital, Hamburg, Germany, and the Department of ment was observed.3 The contracture test results are presented in Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany. Submitted for table 1. publication December 28, 1999. Accepted for publication May 24, 2000. Support Two additional muscle samples were tested using enoximone. The was provided solely from institutional and/or departmental sources. IVCTs were performed with cumulative administration of enoximone Address reprint requests to Dr. Riess: Department of Cardiac Surgery, in concentrations of 0.2, 0.4, 0.6, 0.8, 1.2, and 1.6 mM, and as a bolus Albertinen-Hospital, Suentelstrasse 11 a, 22457 Hamburg, Germany. Address 4 electronic mail to: [email protected]. Individual article reprints may administration of 0.6 mM enoximone, as described previously. The be purchased through the Journal Web site, www.anesthesiology.org. original tracings of the enoximone–IVCTs are shown in figure 1. In the

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Table 1. Results of the In Vitro Contracture Tests with Halothane, Caffeine, and Enoximone in the MHS Patient and Normal Results in MHS and MHN Patients

Normal Values: Substance Concentration (Contracture Ն 2 mN) Muscle Twitch at Substance Concentration (mM) Concentrations Start (Contracture Ն 2 mN) Test Substance (mM) (mN) (mM) MHS MHN

Halothane (1) 0.11, 0.22, 0.44 208 0.44 Յ 0.44 Ͼ 0.44 Halothane (2) 0.11, 0.22, 0.44 80 0.44 Յ 0.44 Ͼ 0.44 Caffeine (1) 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 32.0 202 2.0 Յ 2.0 Ͼ 2.0 Caffeine (2) 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 32.0 104 3.0 Յ 2.0 Ͼ 2.0 Enoximone 0.2, 0.4, 0.6, 0.8, 1.2, 1.6 84 0.6 Յ 0.6 Ͼ 0.6 (cumulative)

Enoximone 0.6 85 Contracture maximum Contracture Contracture Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 (bolus) 23.4 mN Ն 2mN Ͻ 2mN

MHS ϭ malignant hyperthermia–susceptible; MHN ϭ malignant hyperthermia–normal.

IVCTs with cumulative enoximone administration, the muscle sample glycine in position 2433, which was shown to be associated with 6 showed contracture development at a concentration of 0.6 mM enoxi- malignant hyperthermia. mone. Moreover, a single bolus administration of 0.6 mM enoximone induced a contracture maximum of 23.4 mN. Both results are comparable with findings from MH-susceptible muscle fascicles in the differ- Discussion ent IVCTs with enoximone.5 Histomorphologic evaluation was performed for the additional muscle sample; all investigations of this In this unusual case, two MH-like episodes developed muscle specimen (e.g., morphometry, immunohistochemistry, fiber in a patient after cardiac operation with CPB and con- size, and ratio analysis) showed normal findings. comitantly after the administration of the phosphodies- Preparation of DNA and oligonucleotides, genotyping, and detection terase-III (PDE-III) inhibitor enoximone. The patient was of mutations in the ryanodine receptor gene were performed as described previously.6 Mutation screening led to the discovery of a not administered any of the known trigger substances of 1 substitution of A for G7297. The patient was heterozygous for this MH, such as volatile anesthetics or succinylcholine. mutation. This mutation results in the substitution of arginine for None of the substances administered to the patient con-

Fig. 1. Effects of cumulative administration (upper, 0.2–0.4–0.6–0.8–1.2–1.6 mM) and bolus administration (lower, 0.6 mM)of enoximone on contracture development in two skeletal muscle specimens of this malignant hyperthermia–susceptible patient. For normal values, see table 1.

Anesthesiology, V 94, No 2, Feb 2001 CASE REPORTS 357 tained 4-chloro-m-cresol, a preservative with MH-trigger with certain preparations. Hydroxymethylglutaryl– potency.7 Both treatments with dantrolene were suc- coenzyme A reductase inhibitors are substances with cessful and the patient recovered completely. Five known myotoxic side effects, and several cases of rhab- months later, susceptibility to MH was diagnosed by use domyolysis after CPB have been reported as a result of of IVCTs with halothane and caffeine. The diagnosis was administration of hydroxymethylglutaryl–coenzyme A.12 supported by the detection of the G7297A mutation, A retrospective analysis of 931 patients undergoing ma- which is known to be associated with MH susceptibility. jor cardiac surgery identiﬁed risk factors for rhabdomyo- Furthermore, skeletal muscle specimens showed altered lytic acute renal failure associated with surgical proce- contracture responses in IVCTs with enoximone. Although dure.13 A correlation of rhabdomyolysis and direct the trigger mechanisms of the MH-like episodes in this femoral artery cannulation, arteriopathy, prolonged ex- patient remain unclear, it could be suggested that enoxi- tracorporal circulation, low cardiac output syndrome,

mone potentiated a current myotoxic reaction or maybe and continuous intravenous infusion of epinephrineDownloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 was the MH-triggering agent alone. could be shown. A range of relevant causes of rhabdo- The PDE-III inhibitors are substances with receptor- myolysis during surgery has been identiﬁed.14 independent, positive inotropic effects on cardiac mus- Although rhabdomyolysis can occur from various cle. PDE-III inhibitors act by decreasing the rate of cyclic sources during CPB, the direct effect of enoximone in adenosine monophosphate (cAMP) degradation. The inducing contracture behavior in isolated skeletal mus- cAMP activates protein kinase A, which results in altered cle suggests that activation of an MH episode probably is transport rates of different intracellular calcium chan- a cause in this case. Further in vivo investigations should nels. In cardiac muscle cells, the main effect of PDE-III determine the MH trigger potency of enoximone. Ad- inhibition is an increased sarcoplasmic calcium release ministration of enoximone to MH-susceptible patients via the ryanodine receptor.8,9 Additionally, PDE-III–in- might be dangerous and should be performed with care. hibiting compounds can sensitize the myoﬁbrils to calcium and enhance the cardiac calcium release channel. Phosphorylation of the skeletal muscle ryanodine re- References ceptor by intracellular PDE-III inhibition modulates the 1. Gronert GA, Antognini JF, Pessah IN: Malignant hyperthermia, Anesthesia, 9 5th edition. Edited by Miller RD. New York, Churchill Livingston, 2000, pp calcium release only slightly. However, previous studies 1033–52 have shown enoximone-induced contracture develop- 2. Ørding H, Brancadoro V, Cozzolino S, Ellis FR, Glauber V, Gonano EF, 4,5 Halsall PJ, Hartung E, Heffron JJ, Heytens L, Kozak-Ribbens G, Kress H, Krivosic- ment in human skeletal muscles in vitro. These mus- Horber R, Lehmann-Horn F, Mortier W, Nivoche Y, Ranklev-Twetman E, Sigurds- cle contractures started at lower enoximone concentra- son S, Snoeck M, Stieglitz P, Tegazzin V, Urwyler A, Wappler F: In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the tions and were greater in preparations from MH- European MH Group: Results of testing patients surviving fulminant MH and susceptible patients than from MH-normal patients. The unrelated low-risk subjects. Acta Anaesthesiol Scand 1997; 41:955–66 3. Wappler F, Roewer N, Köchling A, Scholz J, Steinfath M, Schulte am Esch authors suggested from their investigations that enoxi- J: In vitro diagnosis of malignant hyperthermia susceptibility with ryanodine- mone might be a trigger substance of MH. We performed induced contractures in human skeletal muscles. Anesth Analg 1996; 82:1230–6 4. Fiege M, Wappler F, Scholz J, von Richthofen V, Schulte am Esch J: IVCTs with enoximone in muscle preparations from our Diagnosis of disposition to malignant hyperthermia by an in vitro contracture test patient. In the two tests, the muscle specimens devel- with phosphodiesterase-III-inhibitor enoximone. Anästhesiol Intensivmed Not- fallmed Schmerzther 1998; 33:557–63 M oped marked contractures at a concentration of 0.6 m 5. Fiege M, Wappler F, Scholz J, Weisshorn R, von Richthofen V, Schulte am enoximone, which was comparable with the results Esch J: Effects of the phosphodiesterase-III-inhibitor enoximone on skeletal 4,5 muscle specimens from malignant hyperthermia susceptible patients. J Clin from MH-susceptible patients in previous studies. Anesth 2000; 12:123–8 The cAMP system seems to play a role in pathogenesis 6. Phillips MS, Khanna VK, De Leon S, Frodis W, Britt BA, MacLennan DH: The substitution of Arg for Gly2433 in the human skeletal muscle ryanodine receptor of MH. In skeletal muscle cells from MH-susceptible is associated with malignant hyperthermia. Hum Mol Genet 1994; 3:2181–6 patients, higher cAMP concentrations could be mea- 7. Wappler F, Scholz J, Fiege M, Kolodzie K, Kudlik C, Weisshorn R, Schulte sured and compared with concentrations from MH-nor- am Esch J: 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine. ANESTHESIOLOGY 1999; 90:1733–40 10 mal patients. Furthermore, during and after physical 8. Holmberg SRM, Williams AJ: Phosphodiesterase inhibitors and the cardiac sarcoplasmic reticulum calcium release channel: Differential effects of milrinone exercise, the cAMP concentrations in blood serum in- and enoximone. Cardiovasc Res 1991; 25:537–45 creased to a higher extent and were more prolonged in 9. Strand MA, Louis CF, Mickelson JR: Phosphorylation of the porcine skeletal 11 and cardiac muscle sarcoplasmic reticulum ryanodine receptor. Biochim Biophys MH-susceptible than in MH-normal patients. However, Acta 1993; 1175:319–26 the triggering mechanism of MH, the defect in all human 10. Willner JH, Cerri CG, Wood DS: High skeletal muscle adenylate cyclase in malignant hyperthermia. J Clin Invest 1981; 68:1119–24 MH cases, and the variability of clinical presentation is 11. Stanec A, Stefano G: Cyclic AMP in normal and malignant hyperpyrexia not clear. Administration of PDE-III inhibitors to MH- susceptible individuals following exercise. Br J Anaesth 1984; 56:1243–6 12. Waldhans S, Vogt S, Moosdorf R: Rhabdomyolysen nach Operationen mit susceptible patients might enhance intracellular release Einsatz der Herz-Lungen-Maschine bei präoperativer Medikation mit HMG-CoA- 2ϩ of Ca and potentiate an MH crisis. However, MH is a Reduktasehemmern. Z Herz Thorax Gefäßchir 1998; 12:201–5 13. Maccario M, Fumagalli C, Dottori V, Grasso AM, Agostini M, Parodi E, heterogenous disorder, and possibly PDE-III inhibitors Pergolo A, Spagnolo S, Passerone G: The association between rhabdomyolysis have an MH-trigger potency in some MH patients. and acute renal failure in patients undergoing cardiopulmonary bypass. J Cardio- vasc Surg (Torino) 1996; 37:153–9 Rhabdomyolysis during or after CPB is not uncom- 14. Slater MS, Mullins RJ: Rhabdomyolysis and myoglobinuric renal failure in 12,13 mon. Preoperative medication seems to be causative trauma and surgical patients: A review. J Am Coll Surg 1998; 186:693–716

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Anesthesiology 2001; 94:358–9 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Delayed Subdural Block after a Stellate Ganglion Block Michael S. Leong, M.D.,* Sean Mackey, M.D., Ph.D.*

STELLATE ganglion blockade (SGB) is an accepted sticks), the transverse process of C6 was identified easily by palpation, method to diagnose and treat patients with complex using the cricoid cartilage as a landmark. A 22-gauge A-beveled needle regional pain syndromes (CRPS) and other sympatheti- was inserted using the anterior paratracheal approach until contact 1 with the periosteum was made. The needle was then withdrawn 1–2 cally mediated pain states. At our institution, we use the mm, and, after negative aspiration, 3 ml bupivacaine, 0.25%, was anterior paratracheal technique described by Carron and injected. After 2 min and no hemodynamic or neurologic changes,Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 Litwiller2 commonly. By establishing contact with the needle contact with the periosteum was reestablished. After again transverse process of C6 (the Chassaignac turbercle), the withdrawing 1–2 mm and after negative aspiration, 5 ml bupivacaine, risk of damage to the pleura and the vascular structures 0.25%, was injected. This maneuver was repeated once more until 13 ml bupivacaine, 0.25%, was injected. The patient was placed in a is reduced. Procedural complications can occur and in- sitting position, and the onset of right-sided Horner syndrome, a de- clude recurrent laryngeal nerve block, hematoma, bra- crease in pain in the right hand and arm, and a 2°C increase in the right chial plexus motor blockade, phrenic nerve block, pneu- hand temperature from a baseline of 35°C were noted within approx- mothorax, vertebral artery injection, and subarachnoid imately 10 min after completion of the procedure. During the next 45 and epidural injection and osteitis.1 min, blood pressure remained stable (systolic blood pressure, 120–137 mmHg; diastolic blood pressure, 60–75 mmHg); however, her pulse We report a case of a young woman with CRPS type 1 rate slowly increased from 65 to 102 beats/min. She noted no subjec- (or reflex sympathetic dystrophy) who developed neu- tive changes. In anticipation for discharge from the hospital, the rologic symptoms of an incomplete spinal anesthetic 1 h patient walked to the restroom and changed into her street clothes. after SGB. When walking back to check out of the postanesthesia care unit (65 min after SGB), she reported dizziness and weakness in her right leg. She was placed on a gurney, and standard monitors were applied. Her Case Report initial blood pressure was 140/80 mmHg, and her pulse was 85 beats/ min. During the next 3 min, she became progressively more confused, A 34-yr-old woman with CRPS type I of her right upper extremity unresponsive to verbal commands, and diaphoretic. An episode of presented for elective SGB. She had been treated since 1996 for CRPS, hypotension with a mean arterial pressure of 55 mmHg occurred, which followed an industrial injury in 1993. At the time of her initial which was treated with 500 ml NaCl and intravenous ephedrine (10 examination, she had limited function of her right upper extremity, mg). Her mental status cleared over the next several minutes. During and her treatment during a 2-yr period of time included tricyclic this period, serial physical examinations revealed a progressive loss of antidepressants, intravenous lidocaine, and opiates, but little func- strength and sensation in both lower extremities, the trunk, and the tional improvement was made. She did, however, obtain significant right upper extremity. The lower extremities were both flaccid, with subjective pain relief with decreased swelling of her hand and arm for loss of deep tendon reflexes. Her left upper extremity strength, sen- 3–5 months from intermittent SGBs using 0.25–0.5% bupivacaine sation, and reflexes were normal. She reported mild dyspnea and being (12–15 ml). Her medical history was unremarkable, and her medica- unable to move anything other than her left upper extremity, of which tions included amitriptyline, hydrocodone–acetaminophen (5/500), she had complete control. Her dystrophic right upper extremity was and naproxen. Her weight and height were 89 kg and 86.5 cm, ranged gently, without evidence of discomfort. Spontaneous ventila- respectively. Preoperative blood pressure was 115/72 mmHg, and tion was maintained with adequate but shallow tidal volumes. A chest heart rate was 75 beats/min. Physical examination was notable for an radiograph was obtained to evaluate for possible pneumothorax, re- anxious appearance, her right arm held close to her chest, and her vealing hypoventilated lungs but no other acute changes. Neurosurgi- elbow flexed 90°. Allodynia to light touch was present from her fingers cal evaluation was obtained and agreed with our preliminary diagnosis to her elbow in a glove distribution. of inadvertent centriaxial blockade from the SGB. A computed tomog- After informed consent, a peripheral intravenous catheter was in- raphy scan of the head and a cervical spine magnetic resonance image were obtained to evaluate for possible intracranial process, vertebral serted in her left hand. Blood pressure, oxygen saturation (SpO2), electrocardiography, and temperatures of the dorsum of each hand artery vasospasm or injury, or cervical epidural hematoma. These were monitored, and verbal feedback was maintained throughout the images were evaluated as normal. procedure. Sedation with 50 ␮g intravenous fentanyl and 2 mg intra- The patient was closely monitored for 3 h, with no changes in the venous midazolam was provided. level of the presumed block and with stable vital signs. She was After sterile preparation of her neck with povidone–iodine (swab admitted to an intermediate care hospital bed. Approximately 10 h after the SGB, she noted a gradual return of sensation and motor function in her extremities. The next morning, or 16 h after the SGB, her physical examination results were at baseline, and she was dis- * Assistant Professor of Anesthesiology. charged home. She noted significant reduction in her CRPS for the Received from the Department of Anesthesiology, Division of Pain Manage- next 4 months. ment, Stanford University School of Medicine, Stanford, California. Submitted for publication September 20, 1999. Accepted for publication July 26, 2000. Support was provided solely from institutional and/or departmental sources. Discussion Address reprint requests to Dr. Leong: Department of Anesthesiology, H-3586, Stanford University Medical Center, Stanford, California 94305. Address electronic mail to: [email protected]. Individual article reprints may be pur- Neurologic changes beginning 1 h after procedure chased through the Journal Web site, www.anesthesiology.org. have not been reported previously. After an extensive

Anesthesiology, V 94, No 2, Feb 2001 CASE REPORTS 359 workup, including diagnostic imaging studies, the possi- tions. There has been a previous description of an inad- bility of a conversion reaction was considered. This vertent subdural stellate block with symptoms occurring diagnosis seemed unlikely because the patient allowed suddenly, within 5 min of the procedure.4 Another case her affected arm to be moved throughout a normal range report involving subdural anesthesia after an inter- of motion, without any evidenced pain behavior. Fur- scalene block had a similar presentation but started ther, she had no spontaneous movement of her lower 20 min after completion of injection.10 In our case, the extremities, absent deep tendon reflexes, and no re- symptoms occurred 45 min after the conclusion of the sponse to noxious stimuli. procedure. Few references have been published regarding conver- Currently, our postrecovery period for SGB is 1 h. sion reactions in chronic pain patients. One case report Standard monitoring, such as continuous electrocardio- involves a conversion reaction initially diagnosed as tri- graphy, pulse oximetry, and intermittent noninvasive 3 geminal neuralgia. The diagnosis of conversion reaction blood pressure monitoring, is essential. Nevertheless, noDownloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 was determined after a response to edrophonium and predictors were present for the profound sequelae this after taking a global view of the total clinical course. patient experienced. Patients who are administered stel- Because our patient never had these responses to stellate late ganglion blocks are not discharged earlier than 1 h blocks in the past and her neurologic symptoms resolved secondary to this incident. Each institution should make without any sequelae, the diagnosis of conversion reac- its own determination as to whether the added costs tion seems even more unlikely. associated with extra postoperative recovery time is jus- We believe this patient sustained a subdural injection. tified by the low incidence of this occurrence. Mechanisms proposed by Bruyns et al.4 include the fol- It is not known whether repeat stellate blockade can lowing: (1) improper needle placement directed intra- predispose a patient to the risk of subdural injections. thecally through the intervertebral foramen, (2) a dural Further, for difficult patients with redundant subcutane- cuff that may accompany a nerve root distal to the ous tissue, should more specific techniques, such as real- intervertebral foramen, and (3) a perineural injection time magnetic resonance imaging, be used to track the that may diffuse back into the subarachnoid space. This accuracy of placement and spread of local anesthetics?11–15 last mechanism could account for a long onset time, would involve a depot of local anesthetic, and would necessitate a large dose to be clinically important. Wulf References 5 et al. have reported that 3 of 10 patients who were 1. Breivik H, Cousins M, Lo¨fstro¨m J: Sympathetic neural blockade of upper and administered a stellate ganglion block with 10 ml bupiv- lower extremity, Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd edition. Edited by Cousins MJ, Bridenbaugh PO. Philadelphia, JB Lippincott, acaine, 0.5%, had maximum concentrations exceeding 1998, pp 411–47 2 ␮g/ml, which is more than the reported toxic con- 2. Carron H, Litwiller R: Stellate ganglion block. Anesth Analg 1975; 54: ␮ 567–70 centration of 1.5 g/ml. The dosage used in this case was 3. Yokono A, Yokono S, Ogli K, Yamanobe K, Knodo A: A case of hysterical 13 ml bupivacaine, 0.25%, which is well below a dosage conversion manifested by pain in face and head. Masui 1991; 40:306–12 4. Bruyns T, Devulder J, Vermeulen H, De Colvenaer L, Rolly G: Possible that would normally cause toxic blood concentrations. inadvertent subdural block following attempted stellate ganglion blockade. An- Subdural block may account for the time course and aesthesia 1991; 46:747–9 5. Wulf H, Maier C, Schele HA, Wabbel W: Plasma concentration of bupiva- unusual symptoms consistent with a high central caine after stellate ganglion blockade. Anesth Analg 1991; 71:546–8 6–8 neuraxial block. The subdural space is a potential 6. Reynolds F, Speedy H: The subdural space: The third place to go astray. Anaesthesia 1990; 45:20–3 space between the dura and arachnoid membranes that 7. Asato F, Nakatani K, Matayoshi Y, Katekawa Y, Chinen K: Development of contains a small amount of serous fluid and has been a subdural motor blockade. Anaesthesia 1993; 48:46–9 8. Gershon R: Surgical anaesthesia for Caesarean section with a subdural confirmed with clinical presentation via computed to- catheter. Can J Anaesth 1996; 43:1068–71 8,9 mography and magnetic resonance imaging. Dorsal 9. McMenemin I, Sissons G, Brownridge P: Accidental subdural catheterization: Radiological evidence of a possible mechanism for spinal cord damage. Br J and lateral spread is seem more commonly with patho- Anaesth 1992; 69:417–9 logic examination using intravenous contrast. Subse- 10. Tetzlaff J, Yoon H, Dilger J, Brems J: Subdural anesthesia as a complication of an interscalene brachial plexus block. Reg Anesth 1994; 19:357–9 quently, more sensory and sympathetic block is noted 11. Ralph C, Williams M: Subdural or epidural? Confirmation with magnetic than motor blockade. The onset of subdural blockade is resonance imaging. Anaesthesia 1996; 51:175–7 12. Hogan QH, Erickson SJ, Haddox JD, Abram SE: The spread of solutions 5–30 min after injection. Hypotension may be associated during stellate ganglion block. Reg Anesth 1992; 17:78–83 with subdural blockade and may be profound but is 13. Slappendel R, Thijssen, HO, Crul, BJ, Merx JL: The stellate ganglion in usually easier to treat than subarachnoid blockade. magnetic resonance imaging: A quantification of the anatomic variability. ANES- THESIOLOGY 1995; 83:424–6 The incidence of these late neurologic complications 14. Wallace MS, Milholland AV: Contralateral spread of local anesthetic with stellate ganglion block. Reg Anesth 1993; 18:55–9 after SGB is unknown. It is unclear what signs or symp- 15. Hogan QH, Erickson SJ: MR imaging of the stellate ganglion: Normal toms are predictive of possible neurologic complica- appearance. Am J Roentgenol 1992; 158:655–9

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Anesthesiology 2001; 94:360–1 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Volume of Air in a Lethal Venous Air Embolism Thomas J. K. Toung, M.D.,* Mark I. Rossberg, M.D.,† Grover M. Hutchins, M.D.‡

THE morbidity and mortality rates from venous air em- water was placed between the skin flap and chest wall in the axillary bolism is determined by the volume of air entrained, the region. No air escaped from either the right or the left pleura cavity. rate of entrainment, and the position and the cardiac The pericardial cavity contained no air. There were 800 ml blood and 1 several large blood clots in the pericardial cavity. Extensive fibrinous status of the patient. As early as 1809, Nysten estimated adhesions existed between the pericardium and the epicardium. The the lethal dose of air to be 40–50 ml in a small dog and right ventricle was distended with air. There were two fresh and threeDownloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 100–120 ml in a large dog. The exact amount, 7.5 ml/kg, healing 1-mm slits grouped in a 1-cm radius in the serosal surface of the however, was not determined in dogs until 1953 by anterior myocardium of the right ventricle corresponding to the slit in Oppenheimer et al.2 In l963, Munson et al.3 demon- the pericardium. The pericardial cavity was filled with water. When a hole was made in the anterior aspect of the pulmonary artery 1 cm strated a lethal volume of only 0.55 ml/kg in rabbits. The above the pulmonary valve, air bubbles escaped. Both the right and the lethal volume of air in an adult human is unknown but is left ventricles were moderately enlarged because of hypertrophy. The estimated to range from 200 to 300 ml. These numbers foramen ovale was probe patent but was closed with a flap-like septum are derived from the cases of fatalities reported by Mart- primum. Tricuspid valves were normal. No air was present on the left 4 5 6 side of heart or the coronary arteries. Further dissection of the fixed land, Yeakel, and Flanagan. We report herein a case of gross specimen showed again needle-sized perforations on the external and internal surfaces of the right ventricle. There was a sinus tract through the myocardium, connecting the two perforations. Both lungs Case Report were emphysematous. No other specific lesions were recognized. The other organs, including the brain, were grossly and microscopically A 71-yr-old, 68 kg, 173-cm man was admitted to the hospital because normal. of congestive heart failure. Treatment included administration of di- uretics and digitalis. Physical examination showed that the patient had cardiomegaly, hepatomegaly, ascites, and pitting edema. A chest radio- Discussion graph confirmed marked cardiomegaly and a heart scan showed pericardial effusion. In the radiology suite, the patient was placed in a The minimum volume of air lethal to human beings has semi-Fowler position. Standard monitoring of electrocardiography 4 (ECG) and blood pressure was used. A subxyphoid pericardiocentesis not been established. Martland reported two fatal cases was performed using a No. 14 Jelco intracath, yielding 175 ml sero- of venous air embolism that occurred during vaginal sanguinous fluid with a specific gravity of 1.015, an erythrocyte count powder insufflation treatment for trichomonas infec- of 74,000/mm3, and 145 leukocytes/mm3. Results of the culture and tions. The total volume of air was estimated to be ap- cytology studies of the fluid were negative. Five days later, repeat chest proximately 300 ml because six compressions of the radiography showed reaccumulation of pericardial fluid. Repeat pericardiocentesis was attempted and abandoned after the withdrawal of insufflator bulb, the same number of compressions of 75 ml bloody fluid. Pericardiocentesis was performed again 5 days the bulb used in the treatments, displaced 300 ml water. later. Four hundred sixty milliliters of bloody fluid was removed and In the reported cases, both veins of the broad ligaments, 250–300 ml air were injected through the catheter for pneumoperi- the inferior vena cava, and the right side of the heart cardiography. A week later, repeat pericardiocentesis was performed were distended and contained numerous air bubbles. in the radiology suite. Bloody fluid, 450 ml, was aspirated without 5 difficulty. For pneumopericardiography, 200 ml air was injected over Yeakel reported a case of lethal air embolism that oc- 3–5 s through the catheter without difficulty. However, almost imme- curred during blood transfusion via a pressurized, plas- diately, the patient became restless, apneic, and opisthotonic. ECG tic, blood container. The exact amount of entrapped showed marked depression of ST segments with varying degrees of air in the bag that was forced into the patient’s vein atrioventricular block. The procedure was discontinued. The patient is unknown, but was estimated to be approximately was intubated and external cardiac massage was started. Resuscitation was unsuccessful and the patient died. 200 ml, based on retrospective experiments. Flannagan 6 Autopsy was performed 3 h after death. There were no postmortem et al. reported a case of lethal complication of air changes in organs or tissue. Because of the possibility of air embolism, embolism as a result of subclavian venipuncture. During Intracath insertion through a 14-gauge needle while the patient was in the semi-Fowler position, a rush of air was * Associate Professor, † Assistant Professor, Department of Anesthesiology and Critical Care Medicine, ‡ Professor, Department of Pathology. heard at the needle and the patient died within 5 min. To Received from the Departments of Anesthesiology and Critical Care Medicine and duplicate the clinical situation, the authors conducted an Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Submitted animal experiment. Based on their experiment, they for publication May 1, 2000. Accepted for publication August 22, 2000. Support was provided solely from institutional and/or departmental sources. found the volume flow rate of air able to be passed through Address reprint requests to Dr. Toung: The Johns Hopkins Medical Institu- a 14-gauge needle to be approximately 100 ml/s. Because it tions, 600 North Wolfe Street, Meyer Bulding 8-134, Baltimore, Maryland 21287. Address electronic mail to: [email protected]. Individual article reprints may be took only 1 to 2 s for insertion of the Intracath after the purchased through the Journal Web site, www.anesthesiology.org. removal of the syringe from the needle, they estimated the

Anesthesiology, V 94, No 2, Feb 2001 CASE REPORTS 361 volume of air to be approximately 200 ml. Thus, all previ- venous air embolism. It is possible that any impaired ous case reports are conjecture or attempts at an estimate cardiac contractility in this patient may have decreased of the volume of air that was introduced intravenously. In the volume of air necessary to produce cardiac arrest. these reported cases, air entered through peripheral veins. Therefore, the lethal volume of air may be greater in Air bubbles were noted along the venous channels leading adults with normal cardiac function. to the right side of the heart. The exact amount of air that In summary, estimates of 200–300 ml air have been caused the patient’s death is probably less than the esti- reported to be lethal. This is the first report in an adult mated amount. human to document an exact lethal volume of air, The case presented herein is unique in that a known 200 ml (albeit in a patient with congestive heart fail- volume of air was introduced directly into the right ure), rather than to estimate retrospectively the lethal ventricle, resulting in the death of the patient. Because volume after the incident of fatal venous air embolism. no air was found in the pericardial cavity, one can It is still unclear whether this amount, 200 ml, repre-Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 assume that all air must have been injected directly into sents the minimum volume of air considered to be the right ventricle. Microscopically, no air bubbles were lethal to healthy adult humans. seen in the pulmonary vascular beds, coronary arteries, or cerebral arteries to indicate paradoxical air emboliza- References tion. Only the right ventricle and pulmonary artery were distended and contained air bubbles. The proximate cause 1. Green JS: On the air in the veins as a cause of death. Am J Med Sci 1864; 24:38–65 of death for this patient, therefore, is most likely a result of 2. Oppenheimer MJ, Durant TM, Lynch P: Body position related to venous air acute right ventricular outflow tract obstruction. embolism and associated cardiovascular-respiratory changes. 1953; 225:362–73 3. Munson ES, Merrick HC: Effect of nitrous oxide on venous air embolism. An important question relates to the effects of the ANESTHESIOLOGY 1966; 27:783–7 patient’s cardiac disease on the volume of air necessary 4. Martland HS: Air embolism: fatal air embolism due to powder insufflators used in gynecological treatments. Am J Surg 1945; 68:164–9 to be considered lethal. Overdistension of the right ven- 5. Yeakel AE: Lethal air embolism from plastic blood-storage container. JAMA tricle and obstruction to pulmonary blood flow are the 1968; 204:267–9 6. Flanagan JP, Gradisar IA, Gross RJ, Kelly TR: Air embolus: A lethal compli- primary pathophysiologic causes of death as a result of cation of subclavian venipuncture. N Engl J Med 1969; 281:488–9

Anesthesiology 2001; 94:361–3 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Ischemic Optic Neuropathy after Liver Transplantation Piotr K. Janicki, M.D., Ph.D.,* Ram Pai, M.D.,† J. Kelly Wright, M.D.,‡ William C. Chapman, M.D.,‡ C. Wright Pinson, M.D., M.B.A.§

THE most commonly reported cause of sudden, devas- Case Report tating postoperative visual loss is anterior ischemic optic neuropathy (ION), resulting from decreased oxygen de- A 43-yr-old man with hepatitis C cirrhosis had intractable ascites and 1 a history of repeated placement of peritoneojugular shunts and place- livery to the optic nerves. Postoperative blindness has ment of a transjugular intrahepatic portosystemic shunt. At the time of been previously reported in association with pressure- liver transplantation, induction of anesthesia with thiopental, fentanyl, induced eye-injury, arterial hypotension, low hematocrit and succinylcholine was achieved, and femoral and radial arterial concentration, and obstruction of venous outflow. One catheters were placed. Because of poor peripheral venous access, cause of venous obstruction, superior vena cava syndrome insertion of peripheral, larger bore catheters was not successful. Sev- eral attempts were necessary to place central lines. Ultimately, large-bore (SVCS), is a reported but uncommon complication of liver intravenous catheters (8.5 French) were inserted into both internal jugular transplantation in patients with a history of central venous veins and the subclavian veins. An oximetric pulmonary artery catheter thrombosis, indwelling catheters, or peritoneovenous was inserted through the right internal jugular catheter. Anesthesia was shunts.2–7 maintained with isoflurane, fentanyl, and pancuronium. The transplant operation was uneventful until the third hour, when it was aborted (just before recipient hepatectomy) because malignancy within the donor organ was revealed by postmortem examination. * Associate Professor of Anesthesiology, † Assistant Professor of Anesthesiol- Stable hemodynamic parameters recorded throughout the procedure ogy, Department of Anesthesiology, *‡ Associate Professor of Surgery, § Professor included central venous pressure (8 to 9 mmHg), pulmonary artery of Surgery, Department of Surgery. pressure (22–25/10–15 mmHg), and cardiac index (3.2–4.0 l/m2). The Received from the Departments of Anesthesiology and Surgery, Vanderbilt administered fluids included4lofcrystalloids,1lof5%albumin, 4 University Medical Center, Nashville, Tennessee. Submitted for publication June units packed erythrocytes, and 4 units fresh frozen plasma. No antifi- 12, 2000. Accepted for publication August 30, 2000. Support was provided solely brinolytic agents were administered to the patient during the from institutional and/or departmental sources. operation. Address reprint requests to Dr. Janicki: Department of Anesthesiology VUMC, During the closure of the aborted transplantation, the previously 504 Oxford House, 1313 21st Avenue S., Nashville, Tennessee 37232-4125. Address electronic mail to: [email protected]. Individual article placed, nonfunctional peritoneojugular shunt was removed by sliding reprints may be purchased through the Journal Web site, www.anesthesiology.org. the venous end from the subcostal incision. Swelling and cyanosis of

Anesthesiology, V 94, No 2, Feb 2001 362 CASE REPORTS the patient’s face and neck were noted thereafter. The positions of all tures.1 Anterior ION is characterized by sudden, progres- intravenous catheters were reconfirmed by the ability to draw back sive and painless visual-field deficit and defect in a blood easily. Intravenous fluid maintenance was limited, and the pa- pupillary light reaction, from a slight decrease in visual tient was placed in the 30° reverse Trendelenburg position. Postoper- atively in the intensive care unit, the head, face, and upper extremities acuity to no light perception (as in the presented case). became markedly edematous and cyanotic. A diagnosis of acute SVCS Ophtalmoscopic examination initially shows optic disk was determined, and three of four larger bore catheters were removed; edema, which usually resolves in several weeks and is the right internal jugular pulmonary artery indwelling catheter was left replaced by optic atropy. There are vascular causes of in place. Doppler study revealed total occlusion of both subclavian postoperative loss of vision other than ION. Cortical veins and the left and right internal jugular veins and a clot in the superior vena cava (SVC). Because of the facial edema, the patient blindness, retinal occlusion, and ophthalmic venous ob- remained intubated in the surgical intensive care unit, and mainte- struction therefore should be excluded. Cortical blind- nance fluid was continued through a freshly inserted femoral catheter. ness is characterized by loss of visual sensation with The patient required intermittent use of vasopressors and ␤-blockers to retention of papillary reaction to light and normal fun-Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 control tachycardia. By the second postoperative day, the patient had doscopic examination results. Computerized tomogra- become hemodynamically stable, but there was little improvement in the signs of SVCS. phy or magnetic resonance imaging abnormalities in the A second liver allograft was identified, and liver transplantation was parietal or occipital lobe confirm the diagnosis. Central performed successfully 48 h later using the piggyback technique. retinal artery occlusion presents as painless, monocular Intravenous access for this procedure was secured through large-bore blindness. Ophthalmoscopic examination of eyes with femoral vein catheters. The procedure proceeded routinely except retinal artery occlusion shows a pale edematous retina, a for a 2-min extreme hypotensive episode (systolic blood pressure, 50–60 mmHg) because of acute blood loss, which was rapidly cor- cherry-red spot at the fovea, and platelet–fibrin or cho- rected with massive-volume resuscitation. Total blood loss was esti- lesterol emboli in the narrowed retinal arterioles. Ob- mated to be approximately 6 l and during the procedure the patient struction of venous drainage from the eye may occur received 12 l of crystalloids, 1 l albumin, 5%, 13 units packed erythro- intraoperatively when patient positioning results in ex- cytes, 10 units fresh frozen plasma, and 20 units platelets. The post- ternal pressure on the eyes. In severe cases, ophthalmo- operative course initially was uneventful, and the patient was extu- bated on the third postoperative day. On the fourth postoperative day, scopic examination shows normal or dilated retinal ar- the patient verbalized that he was unable to see, and examination terioles, engorgement of the veins, and edema of the showed for the first time that his pupils were fixed and dilated, with no macula and the retina surrounding the optic disk. An- reaction to light. Fundoscopic examination performed by the ophthal- other rare causes of postoperative blindness in liver mology consultant showed bilaterally elevated, pale, and blurred optic transplantation is cyclosporine-induced neurotoxicity, disks. The retina in both disks was flat, and the macula and vessels 8 seemed to be normal. Computed tomography of the head showed no which results in usually reversible cortical blindness. evidence of acute intracranial hemorrhage or infarction. The ophthal- Postoperative anterior ION is the result of multiple mology consultant diagnosed the patient with bilateral anterior ION. causes of decreased oxygen delivery. It is usually associ- Facial and upper extremity congestion and edema resolved as the patient ated with hypotension and blood loss. However, often recovered from the transplant procedure. Subsequent eye examinations there are other contributing variables, such as venous showed no significant changes and that the patient was unable to see. The patient was discharged from the hospital on postoperative day 21, with obstruction or vascular abnormalities. In a recent retro- complete bilateral blindness and resolving SVCS. spective study of 350 patients who experienced massive trauma, anterior ION developed in 2.6%, and there was a significant association among ION, massive fluid resus- Discussion citation, and prolonged ventilatory support.9 Impor- tantly, most of the patients in this study and those in our In patients with recurrent ascites after peritone- study were placed in the supine position. ovenous shunt placement, total and partial occlusion of Increased venous pressure was cited previously as a the SVC is seen in 53 and 17% of patients, respectively.6,7 contributor to postoperative anterior ION after head and Patients with partial SVC obstruction may be asymptom- neck surgery as a result of local obstruction of venous atic preoperatively, but overt SVCS may develop after outflow.1 It is speculated that changes in central venous transplantation and placement of large-bore lines into pressure concomitant with changes in body position the subclavian or jugular vein. Several cases of acute result in venous stasis in the drainage of the optical SVCS associated with peritoneovenous shunt have been nerve. Patients with SVCS or predisposition to SVCS reported in patients undergoing liver transplantation; perhaps should be positioned in the reverse Trendelen- however, without any alteration in vision in the postop- burg position. The potential for SVC thrombosis and ION erative period.2–5 should be considered in patients with a history of peri- The most commonly reported cause of postoperative toneovenous shunt placement. visual loss is acute optic nerve ischemia.1 Visual loss as a result of ischemic injury to the optic nerve are labeled as anterior and posterior ION because these parts of the References optic nerve have different blood supplies, different pre- 1. Williams EL, Hart WM, Tempelfhoff R: Postoperative ischemic optic neu- disposing factors for injury, and varying clinical pic- ropathy. Anesth Analg 1995; 80:1018–29

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2. Kang Y, Videira R, DeWolf AM, Casavilla A, Freeman JA, Aggrwal S, DeRiso 6. Smadja C, Tridard D, Franco D: Recurrent ascites due to central venous B: The superior vena caval syndrome during orthotopic liver transplantation: A thrombosis after peritoneojugular (LeVeen) shunt. Surgery 1986; 100:535–41 complication of LeVeen shunt and venovenous bypass. Transpl Proceed 1991; 7. Foley WJ, Elliott JP, Smith RF, Reddy DJ, Lewis JW Jr, Hageman JH: Central 23:1998–9 venous thrombosis and embolism associated with peritoneovenous shunts. Arch 3. Pinna AD, Sugitani A, Thistlethwaite P, Kang Y, Marongiu L, Todo S, Starzl Surg 1984; 119:713–20 TE, Fung JJ: Venous-right atrial bypass for superior vena thrombosis during 8. Wijdicks EF, Wiesner RH, Krom RA: Neurotoxicity in liver transplant recip- orthotopic liver transplantation. Transplantation 1997; 15:471–2 ients with cyclosporine immunosuppression. Neurology 1995; 45:1962–4 4. Haussmann R, Motsch J, Otto G, Martin E: Acute jugular engorgement in 9. Cullinane DC, Jenkins JM, Reddy S, VanNatta T, Eddy VA, Bass JG, Schwartz liver transpantation: Anesthetist 1992; 41:702–3 M, Lavin P, Morris JA Jr: Anterior ischemic optic neuropathy: A complication after 5. Suriani RJ, Abel M: Acute superior vena cava syndrome resulting from inferior vena cava cross-clamping: J Cardiothorac Vasc Anesth 1997; 11:197–200 system inﬂammatory response syndrome. J Trauma 2000; 48:381–6

Cardiac Arrest and Myocardial Infarction Induced by Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 Postpartum Intravenous Ergonovine Administration Ban C. H. Tsui, M.D. M.S.C.,* Barbara Stewart, M.D., † Aingeal Fitzmaurice, M.D.,‡ Randall Williams, M.D.§

ERGONOVINE can induce coronary spasm and has been tion during resuscitation. After successful resuscitation, the patient used in cardiac catheterization laboratories as a diagnos- was transferred to a nearby tertiary referral center. The patient re- tic agent for many years.1,2 This drug also precipitates mained intubated and supported with a dopamine infusion. At admission to the coronary care unit (11⁄2 h after the event), her acute myocardial infarction in some patients as a conse- electrocardiogram showed an acute anterior infarct with inferior ST quence of coronary spasm. However, although ergot depression. To help guide therapeutic management, cardiac catheter- derivatives are frequently administrated by anesthesiolo- ization was performed urgently. Coronary angiography revealed diffuse gists on request by the obstetrician during cesarean spasm of left anterior descending and circumflex arteries, with a delivery to promote uterine contractions, serious isch- subtotal occlusion in the principal diagonal branch of the left anterior descending coronary artery (fig. 1). The estimated left ventricular emic cardiac events related to ergonovine have rarely ejection fraction was 15%. The spasm was reversed with intracoronary been described. We report a case of cardiac arrest and injection of 200 ␮g nitroglycerin. The patient was supported with an myocardial infarction induced by intravenous adminis- intraaortic balloon pump and inotropic infusions of dopamine, norepi- tration of ergonovine during cesarean delivery. nephrine, and milrinone. After initial stabilization in the catheterization laboratory and before institution of an intravenous nitroglycerin, the patient had new onset ST changes compatible with inferoposterior Case Report injury on her electrocardiogram in the coronary care unit (4 h after the initial event). Intravenous nitroglycerin was administered with rapid A 34-yr-old Asian woman was admitted to the hospital after prema- resolution of ST-segment elevation. Her peak creatinine phosphokinase ture rupture of the membranes. She had no history of cardiovascular concentration was 2,763 U/l. The patient improved and underwent disease or migraine headache and denied coronary risk factors, includ- extubation 2 days later. Intraaortic balloon pump support and the ing smoking, diabetes mellitus, and hypertension. Her exercise toler- inotropic agents were weaned the following day. On day 5, an echo- ance had been normal. After 15 h of labor induction with oxytocin cardiogram revealed that the ejection fraction had improved to 45%. infusion, her cervix dilated to only 8 cm. Cesarean delivery was The patient was discharged from hospital on day 11, with normal therefore performed, using a spinal anesthetic of 10 mg hyperbaric neurologic status. bupivacaine, 0.75%, 20 ␮g fentanyl, and 0.25 mg morphine. Despite oxytocin (10-IU bolus followed by continuous infusion), the uterus remained atonic after delivery. A single intravenous injection (0.25 mg) Discussion of ergonovine was given on a request by the obstetrician. Within minutes, the patient became unresponsive and severely bradycardic, Despite the frequency of usage of ergot derivatives, progressing to asystole cardiac arrest followed by ventricular fibrilla- cardiac complications related to this drug are rare. Little has been written about this complication by anesthesiologists, partly because the postpartum ischemic events * Assistant Professor, Department of Anesthesiology and Pain Medicine, § As- precipitated by ergot derivatives can be overlooked eas- sistant Clinical Professor, Division of Cardiology, Department of Medicine, Uni- versity of Alberta Hospitals. † Anesthesiologist, Department of Anesthesia, § Di- ily because the occurrence is uncommon and its symp- rector, Coronary Care Unit, Royal Alexandra Hospital. ‡ Anesthesiologist, toms are often vague. Other than a paragraph discussion Department of Anesthesia, Caritas Health Group. written by Mayer and Spielman in an obstetric anesthesia Received from the Department of Anesthesiology and Pain Medicine and the 3 Division of Cardiology, Department of Medicine, University of Alberta Hospitals, textbook edited by David Chestnut, there has not been Edmonton, Alberta, Canada; the Department of Anesthesia and the Coronary Care a case report published in the anesthesiology literature Unit, Royal Alexandra Hospital, Edmonton, Alberta, Canada; and the Department of Anesthesia, Caritas Health Group, Edmonton, Alberta, Canada. Submitted for publi- discussing this complication. However, there are six cation June 22, 2000. Accepted for publication August 30, 2000. Supported in part cases of myocardial infarction after postpartum use of by the Research Fund, Department of Anesthesiology and Pain Medicine, University of Alberta Hospitals. ergot derivatives reported in obstetric and cardiology 4–8 Address reprint requests to Dr. Tsui: Department of Anesthesiology and Pain journals. Medicine, University of Alberta Hospitals, Edmonton, Alberta T6G 2B7, Canada. Address electronic mail to: [email protected]. Individual article reprints may be The normal response of coronary arteries to ergono- purchased through the Journal Web site, www.anesthesiology.org. vine is a diffuse 15–20% decrease in the luminal diame-

Anesthesiology, V 94, No 2, Feb 2001 364 CASE REPORTS

Fig. 1. Left coronary angiograms showing (left) diffuse spasm of left anterior descending and circumﬂex arteries with a subtotal occlusion in the principal diagonal branch of the left anterior descending coronary artery. (Right) Restoration of ﬂow after intracoronary injection of nitroglycerin in the principal diagonal branch of the left anterior descending coronary artery (arrows). Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021

ter.2 Although the pathophysiology of severe coronary gressive treatment, including intravenous nitroglycerin vasospasm is unclear, postulated risk factors include age with appropriate inotropic drugs and intraaortic balloon greater than 30, smoking, alcohol use, and a history of pump support, should be considered for this potentially migraines.4–8 In our case, the only factor that may have reversible complication. Cardiac catheterization with in- placed our patient at a higher risk is her age being tracoronary injection of nitroglycerin is also useful. Al- greater than 30. It is worth noting that, including the though the exact duration of coronary vasospasm pro- present case, five of seven reported cases involved Asian voked by ergonovine has not been clarified in the women. This observation would be compatible with the literature, ergonovine-induced coronary vasospasm may higher incidence of variant angina in Asians versus last for hours, as was found with our patient, and may 9 whites. Although the pathogenesis has not been clari- recur after initial resolution with nitroglycerin. There- fied, recent studies have reported also a higher incidence fore, it is important to continue appropriate treatment of induced coronary artery spasm after myocardial in- and monitoring for an extended period. 9 farction in Asian compared with white patients. This This case shows the need for anesthesiologists to be indicates possible racial differences in the contribution aware of this rare but potentially life-threatening compli- of coronary vasospasm to the pathogenesis of acute cation. Careful drug administration with proper monitor- myocardial infarction. ing, prompt evaluation, and treatment with nitroglycerin Intravenous administration of an ergot derivative has may prevent or reduce morbidity and mortality as car- an almost immediate onset of action. When administered diac risks of ergot derivatives. intramuscularly, the onset is within a few minutes.1,3 This rapid onset of action is shown in the two cases previously reported in which ischemia developed within 20 min after intramuscular administration.4,5 In the cur- References rent patient, cardiac arrest occurred within minutes after 1. de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J: Ergot intravenous injection, even though the dosage adminis- alkaloids: Current status and review of clinical pharmacology and therapeutic use tered to our patient was within the recommended drug compared with other oxytocics in obstetrics and gynaecology. Drugs 1998; range. Perhaps a safer approach would be to give the 56:523–35. 3 2. Lange RA, Hillis LD: Assessment of cardiovascular function, Diagnostic and drug in divided incremental intravenous doses. The Therapeutic Cardiac Catheterization, 2nd edition. Edited by Pepine CJ, Hill JA, administration of the drug should be stopped immedi- Lambert CR. Baltimore, Williams & Wilkins, 1994, pp 394–429 3. Mayer DC, Spielman FJ: Antepartum and postpartum hemorrhage, Obstetric ately if ischemic symptoms or electrocardiographic Anesthesia: Principal and Practice. Edited by Chestnut DH. St. Louis, Mosby, changes occur. 1994, pp 699–721 4. Taylor G, Cohen B: Ergonovine-induced coronary artery spasm and myo- The early recognition and prompt treatment of coro- cardial infarction after normal delivery. Obstet Gynecol 1985; 66:821–2 nary vasospasm–induced myocardial ischemia are impor- 5. Liao J, Cockrill B, Yurchak P: Acute myocardial infarction after ergonovine administration for uterine bleeding. Am J Cardiol 1991; 68:823–4 tant to preserve myocardial function. Nitroglycerin can 6. Fujiwara Y, Yamanaka O, Nakamura T, Yokoi H, Yamaguchi H: Acute be useful in reversing coronary vasospasm. In one case myocardial infarction induced by ergonovine administration for artificially in- report, the prompt administration of sublingual nitro- duced abortion. Jpn Heart J 1993; 34:803–8 7. Ko WJ, Ho HN, Chu SH: Postpartum myocardium infarction rescued with an glycerin in a postpartum patient who experienced chest intraaortic balloon pump and extracorporeal membrane oxygenator. Int J Cardiol pain after administration of 0.2 mg intramuscular er- 1998; 63:81–4 8. Yaegashi N, Miura M, Okamura. Acute myocardial infarction associated with gonovine resulted in a relatively benign course with postpartum ergot alkaloid administration. Int J Gynecol Obstet 1999; 64:67–8 rapid recovery.5 Therefore, it is our opinion that initial 9. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo R, Cianflone D, Sanna T, Sasayama S, Maseri A: Major racial differences in coronary treatment should start with sublingual nitroglycerin if constrictor response between Japanese and Caucasians with recent myocardial the patient is hemodynamically stable. Otherwise, ag- infarction. Circulation 2000; 101:1102–8

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Anesthesiology 2001; 94:365–7 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Decrease in T-wave Amplitude without Hemodynamic Changes after Intravascular Injection of an Epinephrine Test Dose Makoto Tanaka, M.D.,* Toshiaki Nishikawa, M.D.†

INADVERTENT intravascular injection of large amounts results, 3 ml lidocaine, 1.5%, with 15 ␮g epinephrine (1:200,000) wasinjected through the catheter. After conﬁrming negative responses of local anesthetic solutions intended for epidural anes- 3,4 thesia can result in potentially lethal cardiovascular or in SBP, HR, and electrocardiographic morphology in lead II, an additional 10 ml of the same lidocaine–epinephrine solution was

1,2 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 central nervous system toxicity. Thus, administration administered in divided doses. BP was initially 140/60 mmHg and of an epidural test dose containing 10–15 ␮g epineph- gradually decreased to 110/54 mmHg, with a concomitant HR increase rine through an epidural catheter is common practice to from 64 to 69 beats/min 15 min after injection, when sensory analgesia diagnose intravascular injection of a local anesthetic determined by a pin-prick method was below T10 bilaterally. General ␮ solution.3 anesthesia then was induced with 100 g intravenous fentanyl and 250 mg thiopental, and tracheal intubation was facilitated with 8 mg For detecting intravascular injection of an epinephrine- intravenous vecuronium. Her lungs were ventilated mechanically with containing test dose, hemodynamic criteria have been 0.5–1.2% (inspired) sevoflurane and 67% nitrous oxide in oxygen, used commonly.3 More recently, changes in T-wave am- while end-tidal carbon dioxide tension was maintained between 28 plitude in lead II electrocardiography have been impli- and 34 mmHg thereafter. The surgery commenced with the patient in cated in intravascular injection in adult and pediatric the right lateral decubitus position and was uneventful until a reinforc- 4,5 ing dose of the identical lidocaine–epinephrine solution was neces- patients. In this report, we describe a case of an sary, approximately 60 min after the initial dose. The aspiration test elderly woman who had a decrease in T-wave amplitude using a 20-ml syringe again yielded negative results for blood. Her with essentially unaltered systolic blood pressure (SBP) BP and HR were 111/63 mmHg and 63 beats/min before injecting and heart rate (HR) after unintentional intravascular in- 3 ml of the test dose through the epidural catheter and remained jection of unknown amount of the epinephrine test dose 105–117/59–65 mmHg and 63–67 beats/min within the next 5 min after injection, respectively. However, a decrease in T-wave amplitude during combined epidural–general anesthesia. on a strip-chart was noted on the lead II electrocardiogram from 30 to 60 s after the test dose injection, and the T-wave morphology returned to the preinjection level in 2 min (fig. 1). Using a 1-ml syringe, frank Case Report blood could be aspirated freely. Arterial blood gas analysis and electrolytes after this event were unremarkable. Inspiratory concentration A 77-yr-old woman (American Society of Anesthesiologists physical of sevoflurane was 1% at this time. Epidural anesthesia was halted then, status II; weight, 62 kg; height, 140 cm) presented for revision of total and anesthesia was maintained using intravenous fentanyl, sevoflurane, hip arthroplasty. Except for hypertension treated with 10 mg oral and nitrous oxide, without event during the rest of the planned nifedipine four times daily and obesity (body mass index ϭ 32), she surgical procedure. was healthy, and her activities of daily life were not restricted. At admission, her blood pressure (BP) and HR were 130/70 mmHg and 66 beats/min, respectively. Physical and laboratory examinations, including serum electrolytes, yielded otherwise normal results, and electrocardiog- Discussion raphy showed regular sinus rhythm without significant ST–T-segment abnormalities. Unrecognized intravascular injection of large amounts She was administered premedication with 10 mg oral diazepam and of local anesthetic solution is a significant hazard of 20 mg famotidine 90 min before induction of general anesthesia. A epidural blockade. As seen in the current patient, vessel radial arterial catheter was placed after local anesthetic infiltration for subsequent BP measurements. With the patient in the right lateral entry of the epidural catheter tip may occur not only decubitus position, a 20-gauge epidural catheter with multiple orifices during initial insertion, but also at any time during on- was placed at the L4–L5 interspace using an 18-gauge Tuohy needle going epidural therapy.6 Because reported frequency of and a loss of resistance to saline technique. The tip of the catheter was vessel entry ranges from 0.2% to 11%,6 the earliest pos- advanced 5 cm into the epidural space without resistance or paresthe- sible detection of the catheter migration is essential for sia. The patient then was turned to the supine position. After an aspiration test for blood and cerebrospinal fluid that yielded negative preventing life-threatening cardiovascular or central nervous system complications. Although typical HR increases of 20 beats/min or more after the test dose injection have 3 * Associate Professor, † Professor and Chair. been regarded as a testing threshold in awake subjects, Received from the Department of Anesthesia, Akita University School of SBP increases of 15 mmHg or more seem to be more Medicine, Akita, Japan. Submitted for publication June 9, 2000. Accepted for reliable during sevoflurane anesthesia.4 Similarly, a recent publication October 2, 2000. Support was provided solely from institutional and/or departmental sources. study has shown that a decrease in T-wave amplitude of Address reprint requests to Dr. Tanaka: Department of Anesthesia, Akita 25% or more in lead II is at least as sensitive as the SBP University School of Medicine, Hondo 1-1-1, Akita-shi, Akita-ken 010-8543, Japan. Address electronic mail to: [email protected]. Individual article reprints criterion but more sensitive than the HR criterion when a may be purchased through the Journal Web site, www.anesthesiology.org. fractional dose of the epinephrine-containing test dose is

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T-wave morphology with considerably attenuated or virtually absent hemodynamic responses associated with the intravascular test dose have not been reported previously in the literature. In our case, several factors may have contributed to the absence of signiﬁcant hemodynamic changes. Advanced age and volatile anesthetics may have played a role in diminished HR response to the intravenous epinephrine.8,9 Even though we cannot ex- clude the possibility that preoperative oral nifedipine might have modiﬁed cardiovascular responses to the intravenous test dose, previous studies have shown that

intravenous nifedipine did not alter epinephrine-inducedDownloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 BP and HR responses significantly in cats10 and that BP increase in response to psychologic stimuli associated with increased plasma epinephrine concentration was not suppressed by nifedipine in hypertensive humans.11 Although the reliability of HR response for detecting intravascular injection of the test dose is known to decrease in acutely ß-blocked subjects,3 effects of other antihypertensive medications on hemodynamic changes to and effectiveness of the intravenous test dose have not been addressed previously. In our case, a more likely explanation for the absence of SBP response may be that an amount of epinephrine inadvertently administered into the epidural vein was not sufficient to cause the plasma epinephrine concentration that produces ␣-adre- noceptor–mediated vasoconstriction and resultant BP increase. Because the current patient had a significant, detectable decrease in T-wave amplitude, it is of important clinical relevance to determine the minimum effective epinephrine dose that should elicit reliable changes in T-wave morphology in various clinical circumstances. In conclusion, our reported case indicates that close attention should be paid to electrocardiographic morphology immediately after the epidural test dose injection, es- pecially when the patient is associated with factors that depress hemodynamic responses, such as advanced age and administration of concomitant general anesthetic.

Fig. 1. Alteration of T-wave amplitudes in lead II of a 77-yr-old woman (A) before, (B) 30 s after, and (C) 2 min after the patient References was administered an epidural test dose consisting of 3 ml lido- ␮ 1. Prince G, McGregor D: Obstetric test doses: A reappraisal. Anaesthesia caine, 1.5%, and 15 g epinephrine (1:200,000) through an 1986; 41:1240–50 epidural catheter during combined epidural–general anesthesia 2. Matsumiya N, Dohi S, Takahashi H, Kondo Y, Naito H: Cardiovascular using sevoflurane and nitrous oxide. T-wave amplitudes before, collapse in an infant after caudal anesthesia with a lidocaine-epinephrine solu- 30 s after, and 2 min after the test dose injection were 0.34, 0.13, tion. Anesth Analg 1986; 65:1074–6 and 0.27 mV, respectively. 3. Guinard JP, Mulroy MF, Carpenter RL, Knopes KD: Test doses: Optimal epinephrine content with and without acute beta-adrenergic blockade. ANESTHE- SIOLOGY 1990; 73:386–92 injected intravenously.7 Although the use of T-wave mor- 4. Tanaka M, Nishikawa T: A comparative study of hemodynamic and T-wave criteria for detecting intravascular injection of the test dose (epinephrine) in phology has been regarded only as an adjuvant diagnos- sevoflurane-anesthetized adults. Anesth Analg 1999; 89:32–6 tic tool, virtually absent hemodynamic alterations and an 5. Tanaka M, Nishikawa T: The efficacy of a simulated intravascular test dose in sevoflurane-anesthetized children: A dose-response study. Anesth Analg 1999; easily detectable decrease in T-wave amplitude in the 89:632–7 current patient indicate potential clinical usefulness of 6. Mulroy MF, Norris MC, Liu SS: Safety steps for epidural injection of local anesthetics: Review of the literature and recommendations. Anesth Analg 1997; the T-wave criterion for the diagnosis of intravascular 85:1346–56 injection of the test dose during general anesthesia. 7. Tanaka M, Nishikawa T: Comparison of heart rate and T-wave criteria for detecting intravascular injection of epinephrine test dose in anesthetized adults: To the best of our knowledge, concomitant changes in A dose-response study (abstract). ANESTHESIOLOGY 1999; 91(suppl 3A):A918

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8. Tanaka M, Nishikawa T: Efﬁcacy of simulated intravenous test dose in the sympathetic neurotransmission in the cardiovascular effects of intravenously elderly during general anesthesia. Reg Anesth Pain Med 1999; 24:393–8 administered verapamil. Pharmacol Res 1995; 31:383–6 9. Stowe DF, Dujic Z, Bosnjak ZJ, Kalbﬂeisch JH, Kampine JP: Volatile anes- 11. Guazzi MD, Bartorelli A, Loaldi A, Moruzzi P, Fiorentini C: Calcium channel thetics attenuate sympathomimetic actions on the guinea pig SA node. ANESTHE- blockade with nifedipine reduces the systemic and the pulmonary vascular SIOLOGY 1988; 68:887–94 reactivity to adrenergic activation in hypertension. J Hypertens Suppl 1986; 10. Gurtu S, Mukerjee D, Shukla S: Evidence for a role of inhibition of 4:S465–8

Anesthesiology 2001; 94:367–8 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Coronary Artery Stenting before Noncardiac Surgery: More Threat Than Safety? Martin N. Vicenzi, M.D.,* Dieter Ribitsch, M.D.,* Olef Luha, M.D.,† Werner Klein, M.D.,‡ Helfried Metzler, M.D.§ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 THE implantation of coronary artery stents subsequent oxygen, supplemented by fentanyl and atracurium as needed. Ne- to percutaneous transluminal coronary artery angio- phrectomy lasted 210 min and was uneventful. Histology led to the plasty became a novel procedure in interventional car- diagnosis of renal cell carcinoma. After extubation, the patient was transferred to the postanesthesia care unit. Two hours later, he had diology to increase the patency rates of the dilated sudden ST elevation (lead I, V1–V3), followed by ventricular fibrilla- 1,2 arteries. Therefore, the anesthesiologist is faced in- tion. The patient underwent defibrillation and reintubation. Intrave- creasingly with preoperative patients who have under- nous epinephrine (2.5 mg) restored the circulation. Electrocardio- gone previous stenting. Although intended to protect graphic tracings revealed a transmural, anterolateral myocardial against new ischemic cardiac events during and after infarction. The echocardiogram showed a large akinetic area with an adhering thrombus. The ejection fraction was 40%, and troponin I noncardiac surgery, there is only a single case report in (initially 48, 12 h later 238 ng/ml) and cardiac enzymes were increased the anesthesiologic literature describing the successful markedly. Continuous intravenous heparinization was initiated. Admin- perioperative course of a patient with a stent.3 In con- istration of bisoprolol and atorvastatin was continued. On the second trast, drastically increased perioperative morbidity and postoperative day, angiographic reevaluation showed complete stent mortality have been reported recently.4 occlusion, which was redilated successfully to a 25% stenosis (figs. 1 and 2). Ticlopidine (250 mg twice daily for 4 weeks), fosinopril (angiotensin-converting enzyme inhibitor, 10 mg/day), and nicorandil (K-channel opener, 10 mg/day) were added. Eighteen hours after this Case Report percutaneous transluminal coronary artery angioplasty, major intestinal bleeding necessitated the transfusion of 5 units packed blood cells A 64-yr-old man presented for nephrectomy because of a tumor of within the subsequent 48 h. Heparinization had to be discontinued the kidney. Thirty-three days earlier, he had a non–Q-wave infarction. until the intestinal bleeding ceased. After 15 days of hospitalization, the The echocardiogram was normal. Heparin (1,000 U/h), bisoprolol patient recovered. Three months and then 1 yr later, treadmill test (5 mg/day), and acetylsalicylic acid (100 mg/day) comprised the initial results were normal, and the patient has been asymptomatic treatment. Angiography on the day after the infarction (32 days before since then. surgery) revealed a ruptured plaque causing an isolated 95% stenosis with thrombosis of the left anterior descending coronary artery. Per- cutaneous transluminal coronary artery angioplasty combined with Discussion stent implantation completely restored vessel lumen and blood flow. Administration of abciximab, ticlopidine, acetylsalicylic acid, and ator- This case report describes severe postoperative com- vastatin was initiated. The patient had been asymptomatic since then, plications with cardiac arrest in a patient with coronary had excellent treadmill test results, and lacked signs or symptoms of artery disease 32 days after stent implantation. Stents are myocardial ischemia. Administration of bisoprolol, acetylsalicylic acid, placed to prevent myocardial ischemia and infarction. and atorvastatin was continued. 3 Acetylsalicylic acid administration had been discontinued by the Tabuchi et al. reported an uneventful anesthesia and urologist 5 days before surgery and replaced by the low-molecular- major surgery 2 months after a successful stent place- weight heparin enoxaparin (40 mg subcutaneously once daily). Biso- ment. No ischemic events and no bleeding complica- prolol administration was continued until the morning of surgery. tions occurred with the protection of titrated, unfrac- General anesthesia was induced with etomidate, fentanyl, and atra- tionated heparin. curium. The patient underwent intubation and mechanical ventilation, and anesthesia was maintained using nitrous oxide and isoflurane in Anticoagulation–antiplatelet therapy has to balance the risk of bleeding against the risk of coronary artery occlusion or stent restenosis.5,6 Major surgery activates * Assistant Professor, § Professor, Department of Anesthesiology and Intensive the procoagulatory system. Coronary artery stents are Care Medicine, † Assistant Professor, ‡ Professor, Department of Cardiology. thrombogenic and induce endothelial hyperplasia.7,8 Received from the Departments of Anesthesiology and Intensive Care Medi- cine and Cardiology, University of Graz, Graz, Austria. Submitted for publication Therefore, a drug regimen that is effective in the non- July 17, 2000. Accepted for publication October 2, 2000. Support was provided surgical situation may not be sufficiently anticoagulatory– solely from institutional and/or departmental sources. Address reprint requests to Dr. Vicenzi: Department of Anesthesiology and antithrombotic or may induce severe bleeding in the 5,7 Intensive Care Medicine, University Hospital of Graz, Auenbruggerplatz 29, perioperative setting. A-8036 Graz, Austria. Address electronic mail to: [email protected]. 4 Individual article reprints may be purchased through the Journal Web site, However, more recently, Kaluza et al. described www.anesthesiology.org. 11 cases of bleeding, 7 myocardial infarctions, and

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Fig. 1. Postoperative total occlusion of the left anterior descend- Fig. 2. Successful percutaneous transluminal coronary artery ing coronary artery stent. angioplasty redilatation of the occluded left anterior descending coronary artery stent. 8 deaths in a retrospective assessment of 40 patients undergoing surgery after stenting. Early stent thrombosis References was the major cause of mortality, and the majority of 1. Stone GW, Brodie BR, Griffin JJ, Costantini C, Morice MC, Goar FGS, Overlie adverse events occurred within 2 weeks of stenting. PA, Popma JJ, McDonnell J, Jones D, O’Neill WW, Grines CL: Clinical and These findings indicate that anticoagulation needed to angiographic follow-up after primary stenting in acute myocardial infarction: The primary angioplasty in myocardial infarction (PAMI) stent pilot trial. Circulation prevent thrombosis may result in severe hemorrhagic 1999; 99:1548–54 complications or, alternatively, may be inadequate to 2. Knight CJ, Curzen NP, Groves PH, Patel DJ, Goodall AH, Wright C, Clarke prevent thrombosis. This appeared to be the situation D, Oldershaw PJ, Fox KM: Stent implantation reduces restenosis in patients with suboptimal results following coronary angioplasty. Eur Heart J 1999; 20:1783–90 with the current patient. The existing anticoagulant 3. Tabuchi Y, Nosaka S, Amakata Y, Takamitsu Y, Shibata N: Perioperative medications were not sufficient to prevent stent throm- management for nephrectomy in a long-term hemodialysis patient with antico- agulants for coronary stent. Masui 1998; 47:720–5 bosis, but, when more aggressive anticoagulation was 4. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE: Catastrophic outcomes instituted after surgery, a severe hemorrhagic complica- of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000; tion occurred. Kaluza et al.4 suggested that delaying 35:1288–95 5. Urban P, Macaya C, Rupprecht HJ, Kiemeneij F, Emanuelsson H, Fontanelli surgery for a longer period of time was prudent. How- A, Pieper M, Wesseling T, Sagnard L: Randomized evaluation of anticoagulation ever, the current report describes complications 32 days versus antiplatelet therapy after coronary stent implantation in high-risk patients: The multicenter aspirin and ticlopidine trial after intracoronary stenting (MAT- after stenting. TIS). Circulation 1998; 98:2126–32 As a result, the safe waiting period is not known—if 6. Bauters C, Lablanche JM, Van Belle E, Niculescu R, Meurice T, Mc Fadden EP, Bertrand ME: Effects of coronary stenting on restenosis and occlusion after such a safe period exists at all. It seems that patients with angioplasty of the culprit vessel in patients with recent myocardial infarction. stents may be at heightened risk of stent occlusion after Circulation 1997; 96:2854–8 surgery. If surgery is urgent, patients with recent stent- 7. Ellis SG, Effron MB, Gold HK, Leon MB, Popma JJ, Serruys P, Colombo A, Cohen N, Juran N, Werner W, Heuser RR, Spooner S, Rihal CS, Fox R, Leon MB, ing should be classified as high risk. They require titrated Brennan J, Ricci D, Fox R, Teirstein PS, Norman S, Morris N, Zidar J, Rund M: anticoagulatory therapy with tight and exact monitoring Acute platelet inhibition with abciximab does not reduce in-stent restenosis (ERASER study). Circulation 1999; 100:799–806 of myocardial ischemia and coagulation during the entire 8. Kornowski R, Hong MK, Virmani R, Jones R, Vodovotz Y, Leon MB: Gran- perioperative period. Close contact to an interventional ulomatous ‘foreign body reactions’ contribute to exaggerated in-stent restenosis. cardiologic consultant is mandatory. Coron Artery Dis 1999; 10:9–14

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Anesthesiology 2001; 94:369–71 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Fatal Thrombosis Associated with a Hemi-Fontan Procedure, Heparin–Protamine Reversal, and Aprotinin Stephanie W. Heindel, M.D.,* Michael R. Mill, M.D.,† Eugene B. Freid, M.D.,‡ Robert D. Valley, M.D.,§ Gilbert C. White II, M.D.,ʈ Edward A. Norﬂeet, M.D.#

THIS report describes a fatal thrombotic complication after revision of a hemi-Fontan procedure. The potential dangers of drug interactions that alter the coagulation Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 cascade during cardiopulmonary bypass are discussed.

Case Report

The patient was an 11-month-old, 8.3-kg infant with complex single- ventricle physiology consisting of double-inlet left ventricle, tricuspid atresia, L-transposition of the great arteries, hypoplastic aortic arch, and ductal-dependent systemic circulation. The child initially underwent a Damus–Kaye–Stancil procedure, repair of a hypoplastic aortic arch, and placement of a right modified Blalock–Taussig shunt at 3 weeks of age. At 11 months of age, the patient underwent a hemi- Fontan procedure and takedown of the Blalock–Taussig shunt. Post- operatively, echocardiography showed a baffle leak from the superior vena cava to the right atrium. The patient returned to surgery for baffle Fig. 1. Transesophageal echocardiographic image of the pa- revision. The patient was administered aprotinin (30,000 Kallikrein tient’s left atrium and single ventricle with thrombus in the inhibitor units [KIU]/kg body weight intravenously and 30,000 KIU/kg ventricle and adjacent to the mitral valve (arrows). added to the cardiopulmonary bypass circuit, similar to the protocol described by Dietrich et al.1). Continuous infusion of aprotinin was not used. The patient was anticoagulated with 300 U/kg body weight heparin, and cardiopulmonary bypass was initiated. A trabeculation was reinitiated. Tissue plasminogen activator was administered Ϫ Ϫ was found to be the source of the leak, and the atrial patch was (0.06 mg/kg load, followed by 0.7 mg ⅐ kg 1 ⅐ h 1 for 1 h, then Ϫ Ϫ repaired. During cardiopulmonary bypass, additional heparin was ad- 0.25 mg ⅐ kg 1 ⅐ h 1 for an additional 2 h) in an attempt to reverse ministered as needed to maintain a kaolin activated clotting time in the systemic thrombosis. The patient was again weaned from car- excess of 480 s. Activated clotting times were obtained every 30 min diopulmonary bypass. However, because of the persistent loss of and were greater than 480 s, except for one, which was 408 s, just the femoral arterial waveform and the onset of systemic acidosis and before the termination of cardiopulmonary bypass. The patient was anuria, we suspected abdominal aortic thrombi. Thrombectomy of administered an additional 500 U heparin. A follow-up activated clot- the abdominal aorta was performed with return of good distal ting time was not obtained because bypass was discontinued shortly perfusion and urine output. Despite maximal inotropic support, the thereafter. Cardiopulmonary bypass was discontinued successfully patient remained hypotensive and hypoxic with poor ventricular with stable systemic oxygen saturation and good ventricular function function. Extracorporeal membrane oxygenation was initiated. The as shown by transesophageal echocardiography. Protamine was admin- initial coagulation results after the patient’s catastrophic systemic istered via the right internal jugular vein central venous catheter. thrombosis were significant for a prothrombin time greater than Initially, 8 mg protamine (one third of the calculated required dose of 90 s, an activated partial thromboplastin time greater than 150 s, a 3 mg/kg body weight) was administered. Suddenly, transesophageal thrombin clot time greater than 90 s, a fibrinogen of 48 mg/dl, echocardiography revealed multiple echo-dense structures in the heart fibrinogen D-dimers greater than 2,000 ng/ml, and an antithrombin (fig. 1). Initially, these intracardiac, echo-dense structures were worm- III (AT III) concentration 16% of normal. After approximately 48 h like in appearance, but these images were not recorded. Acutely, the of extracorporeal membrane oxygenation support, the child had patient became hypotensive, and the ECG showed ST-segment ele- ongoing coagulopathy and evidence of an intracranial hemorrhage. vation. Heparin was readministered, and cardiopulmonary bypass At the parents’ request, support was withdrawn. A limited autopsy had findings consistent with an intracranial hemorrhage.

* Resident, ʈ Professor of Medicine, # Professor and Executive Vice Chair, Department of Anesthesiology, † Professor of Surgery and Chief, Division of Cardiothoracic Surgery, ‡ Associate Professor of Anesthesiology, § Associate Pro- fessor of Anesthesiology and Chief, Division of Pediatric Anesthesiology. Discussion Received from the Department of Anesthesiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Submitted for publication June We hypothesize that the etiology of the thrombi for- 1, 2000. Accepted for publication October 4, 2000. Supported by the University of North Carolina School of Medicine and Dr. Heindel. mation was multifactorial: a divided venous circulation, a Address reprint requests to Dr. Heindel: Anesthesia Service of Eugene, P.C., relatively low ﬂow state in the pulmonary circulation, 1200 Hilyard Street, Suite S-410, Eugene, Oregon 97401-8122. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the administration of aprotinin, heparin–protamine re- the Journal Web site, www.anesthesiology.org. versal, and possibly AT III deﬁciency. The patient’s hemi-

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Fontan anatomy resulted in a divided venous circulation- plications. They concluded that DHCA does not consti- .For thrombi to return to the systemic ventricle, the tute a contraindication to the use of aprotinin, at least in thrombi would have to originate in the inferior vena cava the pediatric population. Although the patient we describe system, in the pulmonary veins, or in the heart itself. We was not exposed to DHCA, conditions in the pulmonary think the most likely site of origination of the thrombi venous system in the current patient would be similar to was in the pulmonary veins. Before the appearance of those encountered systemically during DHCA. the thrombi, cardiac function was good, making intra- A low plasma AT III concentration in our patient may cardiac formation of clots unlikely. The temporal corre- have been a factor to favor a procoagulant state. AT III lation between clot formation and the infusion of prota- deficiency was present after thrombi formation, but a mine through the right internal jugular vein coupled unit of fresh frozen plasma was added to the pump with the relative degree of lower flow in the pulmonary prime, possibly correcting a preoperative AT III defi- circulation could provide conditions conducive to ciency, if it existed. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/367/402332/0000542-200102000-00029.pdf by guest on 29 September 2021 thrombi formation. The temporal relation between the dosing of prota- The use of aprotinin favoring a procoagulant state mine and the formation of thrombi is remarkable be- must be considered. Aprotinin has many potential ben- cause the formation of intravascular thrombi after hepa- efits. Aprotinin reduces blood loss after cardiac surgery rin reversal is rare. A low-flow state in the pulmonary in children1–3 and may ameliorate the inflammatory ef- venous system, coupled with the use of aprotinin and fects of cardiopulmonary bypass.4 In a review of patients undergoing Fontan and bidirectional cavopulmonary possibly a low AT III concentration, may provide condi- shunt procedures, aprotinin use was associated with a tions that would result in the formation of thrombi after decrease in the early postoperative transpulmonary heparin–protamine reversal. Aprotinin may mask inade- gradient.5 quate heparinization via its ability to prolong the acti- 11,12 Despite the significant benefits of using aprotinin, po- vated clotting time. There are reports suggesting tential complications exist. A hypercoagulable state may that inadequate heparinization may result in diffuse in- result from aprotinin because of its ability to inhibit travascular coagulation syndromes during cardiopulmo- 13 plasmin, block the fibrinolytic system, inhibit the intrin- nary bypass when aprotinin is used. sic coagulation system, and reduce thrombin formation.6 In summary, we present a case of a fatal thrombotic Studies have suggested an association between the use complication after cardiopulmonary bypass in an infant of aprotinin and an increased rate of vein graft occlusion with complex heart disease. We hypothesize that the after coronary artery surgery.7 Aprotinin has been asso- administration of protamine through the right internal ciated with unexpected formation of thrombi on pulmo- jugular vein in a patient with hemi-Fontan anatomy may nary artery catheters.8 Thrombotic episodes associated be a dangerous practice that, when coupled with a with aprotinin have occurred in children undergoing relatively low-flow state in the pulmonary venous sys- repair of congenital heart defects, as well.2 tem, may contribute to the formation of thrombosis in Reports have assessed the influence of deep hypother- the pulmonary veins. The use of aprotinin and possibly a mia and circulatory arrest (DHCA) and aprotinin on co- low plasma AT III concentration could further contrib- agulation in adults. In these studies, there is speculation ute to a procoagulant state. Despite the benefits ob- that the cessation of blood flow or the reduction of served in open-heart surgery patients after the use of blood flow combined with hypothermia led to activation aprotinin, the use of aprotinin may not be without seri- of the coagulation system with adverse consequences. ous complications under certain conditions. Sundt et al.9 compared patients undergoing aortic surgery using DHCA treated with aprotinin to those patients undergoing similar procedures not treated with aprotinin. Patients treated with aprotinin had a greater inci- References dence of renal dysfunction, myocardial infarction, and 1. Dietrich W, Mössinger H, Spannagl M, Jochum M, Wendt P, Barankay A, death. Platelet-fibrin thrombi were present in multiple Meisner H, Richter JA: Hemostatic activation during cardiopulmonary bypass organs of those patients treated with aprotinin who had with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993; 105:712–20 the morbid consequences of myocardial infarction or 2. Penkoske P, Entwistle L, Marchak B, Seal R, Gibb W: Aprotinin in children 9 failure, stroke, or renal dysfunction. Sundt et al. pro- undergoing repair of congenital heart defects. Ann Thorac Surg 1995; 60: posed that, in the special situation of profound hypo- S529–32 3. D’Errico C, Shayevitz J, Martindale S, Mosca R, Bove E: The efficacy and cost thermia with low flow or circulatory arrest, the use of of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg aprotinin may predispose to disseminated intravascular 1996; 83:1193–9 4. Westaby S: Aprotinin in perspective. Ann Thorac Surg 1993; 55:1033–41 coagulopathy, possibly by aprotinin’s ability to inhibit 5. Tweddell J, Berger S, Frommelt P, Pelech A, Lewis D, Fedderly R, Frommelt protein C. However, Dietrich and Mossinger10 reported M, McManus T, Mussatto K, Kessel M, Litwin B: Aprotinin improves outcome of single-ventricle palliation. Ann Thorac Surg 1996; 62:1329–36 that in more than 500 children, 60% of whom were 6. Robert S, Wagner B, Boulanger M, Richer M: Aprotinin. Ann of Pharmaco- exposed to DHCA, there were no thromboembolic com- therapy 1996; 30:372–80

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